Sickle cell trait (HbAS) is known to be protective against Plasmodium falciparum malaria, but it is unclear when during the course of infection protection occurs and whether protection is innate or acquired.

To address these questions, a cohort of 601 children aged 1-10 was enrolled in Kampala, Uganda, and followed for 18 months for symptomatic malaria and asymptomatic parasitemia. Genotyping was used to detect and follow individual parasite clones longitudinally within subjects. Children with HbAS were protected against establishment of parasitemia, as assessed by the molecular force of infection, at older but not younger ages (2 years old: incidence rate ratio [IRR] 1.16, 95%CI 0.62-2.19, p=0.6; 9 years old: IRR 0.50, 95%CI 0.28-0.87, p=0.01) suggesting an acquired mechanism of protection. Once parasitemic, children with HbAS were less likely to progress to symptomatic malaria, with protection again most pronounced at older ages (2 years old: RR 0.92, 95%CI 0.77-1.10, p=0.3; 9 years old: RR 0.68, 95%CI 0.51-0.91, p=0.008). Conversely, the youngest children were best protected against high parasite density (2 years old: relative density = 0.24, 95% CI 0.10-0.54, p=0.001; 9 years old: relative density = 0.59, 95%CI 0.30-1.19, p=0.14) suggesting an innate mechanism of protection against this endpoint.